Treating severe malaria: What to know about artesunate

Malaria is a global health problem, with an estimated 3.3 billion people living in more than 106 countries and territories at risk for the disease.

According to WHO, 219 million clinical episodes and 660,000 deaths were attributed to malaria in 2010. Although malaria was successfully eradicated in the United States in the early 1950s, there are 1,500 cases reported annually, mostly in returning travelers and immigrants. The vectors of malaria, Anopheles mosquitoes, exist in the United States; therefore, there is a persistent risk of a re-emergence of malaria transmission within our own borders.

Symptoms of malaria parasite infection can present in various ways, ranging from nearly asymptomatic to a life-threatening medical emergency. If treatment is delayed, the disease can rapidly progress (sometimes within hours) to life-threatening complications, such as neurologic abnormalities (including coma), severe anemia, acute respiratory distress syndrome, coagulopathies, metabolic acidosis, hypoglycemia and organ failure. It is imperative to initiate life-saving treatment as soon as possible because the mortality rate of untreated severe malaria is nearly 100%.

In the crucial moments after a malaria diagnosis, providers in the United States may face a significant issue of obtaining appropriate, timely treatment. The only FDA-approved parenteral medication for the treatment of malaria is IV quinidine. Quinidine is the D-isomer of quinine, the oldest known antimalarial drug that is a component of the bark of cinchona trees. Classified as a class IA antiarrhythmic, quinidine has been shown to be an effective treatment for severe malaria, but it comes with many obstacles. First, the decreased availability of the drug at many US hospitals has been problematic. As new, more favorable antiarrhythmics have come to the market, fewer institutions are keeping quinidine on their shelves and on their formulary. Delays in acquiring quinidine from the manufacturer for severe malaria cases have been cited as a contributing factor for fatalities in the United States and Canada. Second, there is a high risk of cardiotoxic adverse effects, including QRS widening, QT prolongation and persistent hypotension. These adverse events make the use of quinidine contraindicated in patients with heart block or other conduction defects. Yet another issue with quinidine use is the report of increasing resistance in Southeast Asia, although this has not been reported yet in the United States.

First-line treatment

According to WHO’s 2010 guidelines, artesunate is the first-line drug of choice over quinine and quinidine for severe P. falciparum malaria in adult and pediatric patients. Although it is not FDA-approved, artesunate has been available in the United States since June 2007 through an investigational new drug protocol and/or as an emergency use medication. The drug can only be obtained through the CDC and is restricted to patients who have severe malaria, high levels of parasitemia, are unable to take oral medications, do not have timely access to IV quinidine, have contraindications or intolerance to quinidine or those who have failed quinidine therapy.

Artesunate is a derivative of artemisinin, a Chinese herbal medicine that is extracted from the sweet wormwood plant. Its use for treating malaria emerged in the 1970s when scientists were researching new options to battle drug resistance. It is hypothesized that artemisinin has antimalarial activity by producing oxygen radicals through cleavage of the endoperoxide bridge, which then interfere with parasite function. Other derivatives include dihydroartemisinin, artemether and arteether, which are available in different formulations and are all approved by WHO for malaria treatment worldwide.

IV artesunate was shown to significantly reduce the risk for death in severe malaria cases compared with IV quinine in six trials that included 1,938 participants, as reported by WHO (RR=0.62; 95% CI, 0.51-0.75). In SEAQUAMAT — a randomized, multicenter, controlled trial with 1,461 participants — the number needed to treat with artesunate to save one life compared with quinine was 11.1 to 20.2 (variations existed between countries). This recommendation also was based on a lower risk of hypoglycemia and easier administration. At the time of WHO’s publication, there were no studies showing a difference in neurological sequelae. Results were similar in the pediatric participants studied in the AQUAMAT trial (n=5,425), which showed a 22.5% mortality reduction rate in the artesunate treatment group.

Another benefit for using artesunate over quinidine is its adverse effect profile. There are few human toxicity studies available; however, observation data and clinical trials have shown that the artemisinin derivatives are well tolerated. Potential adverse effects include urticaria, nausea, vomiting, abdominal pain, decrease in reticulocyte count and increase liver function tests. It should be noted that some adverse events that have been reported in clinical trials are consistent with known adverse effects of other antimalarial medications that were used concomitantly or symptoms of the malaria infection itself.

The recommended artesunate regimen for severe malaria is to give a 2.4-mg/kg dose at the time of admission, followed by a second dose 12 hours after the initial dose and a third dose 24 hours after the initial dose. Any further doses can be administered once daily. IV therapy should be continued for a minimum of 24 hours even if the patient can tolerate oral medications.

After treatment with IV artesunate, patients should continue on what is referred to as “follow-on treatment” with oral medications. In the United States, these options are (in order of preference) atovaquone-proguanil, doxycycline/clindamycin or mefloquine. This continued therapy is not a part of the CDC’s investigational new drug protocol for artesunate and should be left up to the local infectious disease physician’s discretion.

Malaria in the US

Severe malaria is considered a medical emergency and cases are still reported in the United States every year. The only FDA-approved parenteral medication, quinidine, has been difficult to acquire in recent years due to its decreased use for its primary indication as an antiarrhythmic. In addition, WHO recommends using artesunate over quinidine based on clinical evidence showing superior efficacy, reduced mortality, easier administration and improved adverse effect profile. Artesunate is only available through an investigational new drug protocol and/or as an emergency use medication through the CDC, despite it being used routinely worldwide for the past 2 decades. To enroll a patient with severe malaria in the treatment protocol with artesunate, contact the Malaria Hotline at the CDC at 770-488-7788 during business or 770-488-7100 after hours.

References:

CDC. MMWR. 1996;45(23):494-495.
Investigational New Drug Protocol #76725. IV artesunate for treatment of severe malaria in the United States. Revised December 3, 2013.
WHO. Guidelines for the treatment of malaria: Second edition. 2010. Available at: www.who.int/malaria/publications/atoz/9789241547925/en/index.html. Accessed Jan. 16, 2014.

For more information:

Kimberly D. Boeser, PharmD, is an infectious disease clinical pharmacist and antimicrobial stewardship coordinator at the University of Minnesota Medical Center-Fairview and the University of Minnesota Amplatz Children’s Hospital.
Dayla Boldt, PharmD, is a PGY2 infectious disease pharmacy resident at the University of Minnesota Medical Center-Fairview and the University of Minnesota Amplatz Children’s Hospital.

Disclosure: Boeser and Boldt report no relevant financial disclosures.